Implantable device for promoting repair of a body lumen

ABSTRACT

An implantable stent having surface features adapted to promote an organized growth pattern of infiltrating cells when implanted in a tubular organ is provided. The surface features comprise depressions, pores, projections, pleats, channels or grooves in the stent body and are designed to increase turbulence or stagnation in the flow of a liquid, such as blood through the stent, and/or to promote the growth of infiltrating cells in an organized pattern. Alternatively, the invention stent can be populated with living cells prior to implant and can be heatable from an external source of energy, thereby inducing production of therapeutic bioactive agents from ingrowing cells. The invention also provides an implantable heatable stent for transcutaneously monitoring the flow of fluid through a lumen into which the stent is implanted by measuring the rate at which the heated stent cools in response to blood flow when the source of heat is removed.

RELATED APPLICATIONS

This application is a Continuation-In-Part application of U.S. patentapplication Ser. No. 09/139,084, filed Aug. 25, 1998, which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to an implantable medical device; andmore particularly to an implantable stent.

2. Discussion of the Prior Art

Damage to the endothelial and medial layers of a blood vessel, such asoften occurs in the course of balloon angioplasty and stent procedures,has been found to stimulate neointimal proliferation, leading torestenosis of atherosclerotic vessels.

The normal endothelium, which lines blood vessels, is uniquely andcompletely compatible with blood. Endothelial cells initiate metabolicprocesses, like the secretion of prostacylin and endothelium-derivedrelaxing factor (EDRF), which actively discourage platelet depositionand thrombus formation in vessel walls. However, damaged arterialsurfaces within the vascular system are highly susceptible to thrombusformation. Abnormal platelet deposition, resulting in thrombosis, ismore likely to occur in vessels in which endothelial, medial andadventitial damage has occurred. While systemic drugs have been used toprevent coagulation and to inhibit platelet aggregation, a need existsfor a means by which a damaged vessel can be treated directly to preventthrombus formation and subsequent intimal smooth muscle cellproliferation.

Current treatment regimes for stenosis or occluded vessels includemechanical interventions. However, these techniques also serve toexacerbate the injury, precipitating new smooth muscle cellproliferation and neointimal growth. For example, stenotic arteries areoften treated with balloon angioplasty, which involves the mechanicaldilation of a vessel with an inflatable catheter. The effectiveness ofthis procedure is limited in some patients because the treatment itselfdamages the vessel, thereby inducing proliferation of smooth musclecells and reocclusion or restenosis of the vessel. It has been estimatedthat approximately 30 to 40 percent of patients treated by balloonangioplasty and/or stents may experience restenosis within one year ofthe procedure.

To overcome these problems, numerous approaches have been taken toproviding stents useful in the repair of damaged vasculature. In oneaspect, the stent itself reduces restenosis in a mechanical way byproviding a larger lumen. For example, some stents gradually enlargeover time. To prevent damage to the lumen wall during implantation ofthe stent, many stents are implanted in a contracted form mounted on apartially expanded balloon of a balloon catheter and then expanded insitu to contact the lumen wall. U.S. Pat. No. 5,059,211 discloses anexpandable stent for supporting the interior wall of a coronary arterywherein the stent body is made of a porous bioabsorbable material. Toaid in avoiding damage to vasculature during implant of such stents,U.S. Pat. No. 5,662,960 discloses a friction-reducing coating ofcommingled hydrogel suitable for application to polymeric plastic,rubber or metallic substrates that can be applied to the surface of astent.

A number of agents that affect cell proliferation have been tested aspharmacological treatments for stenosis and restenosis in an attempt toslow or inhibit proliferation of smooth muscle cells. These compositionshave included heparin, coumarin, aspirin, fish oils, calciumantagonists, steroids, prostacyclin, ultraviolet irradiation, andothers. Such agents may be systemically applied or may be delivered on amore local basis using a drug delivery catheter or a drug eluting stent.In particular, biodegradable polymer matrices containing apharmaceutical may be implanted at a treatment site. As the polymerdegrades, a medicament is released directly at the treatment site. Therate at which the drug is delivered is dependent upon the rate at whichthe polymer matrix is resorbed by the body. U.S. Pat. No. 5,342,348 toKaplan and U.S. Pat. No. 5,419,760 to Norciso are exemplary of thistechnology. U.S. Pat. No. 5,766,710 discloses a stent formed ofcomposite biodegradable polymers of different melting temperatures.

Porous stents formed from porous polymers or sintered metal particles orfibers have also been used for release of therapeutic drugs within adamaged vessel, as disclosed in U.S. Pat. No. 5,843,172. However, tissuesurrounding a porous stent tends to infiltrate the pores. In certainapplications, pores that promote tissue ingrowth are considered to becounterproductive because the growth of neointima can occlude theartery, or other body lumen, into which the stent is being placed.

Delivery of drugs to the damaged arterial wall components has also beenexplored by using latticed intravascular stents that have been seededwith sheep endothelial cells engineered to secrete a therapeuticprotein, such as t-PA (D. A.

Dichek et al., Circulation, 80, 1347-1353, 1989). However, endotheliumis known to be capable of promoting both coagulation and thrombolysis.

Another approach to controlling the healing of a damaged artery or veinis to induce apoptosis in neointimal cells to reduce the size of astenotic lesion. U.S. Pat. No. 5,776,905 to Gibbons et al., which isincorporated herein by reference in its entirety, describes induction ofapoptosis by administering anti-sense oligonucleotides that counteractthe anti-apoptotic gene, bcl-x, which is expressed at high levels byneointimal cells. These anti-sense oligonucleotides are intended toblock expression of the anti-apoptotic gene bcl-x so that the neointimalcells are induced to undergo programmed cell death.

Under certain conditions, the body naturally produces another drug thathas an influence on cell apoptosis among its many effects. As isexplained in U.S. Pat. No. 5,759,836 to Amin et al., which isincorporated herein by reference in its entirety, nitric oxide (NO) isproduced by an inducible enzyme, nitric oxide synthase, which belongs toa family of proteins beneficial to arterial homeostasis.

However, the effect of nitric oxide in the regulation of apoptosis iscomplex.

A pro-apoptotic effect seems to be linked to pathophysiologicalconditions wherein high amounts of NO are produced by the induciblenitric oxide synthase. By contrast, an anti-apoptotic effect resultsfrom the continuous, low level release of endothelial NO, which inhibitsapoptosis and is believed to contribute to the anti-atheroscleroticfunction of NO. Dimmeler in “Nitric Oxide and Apoptosis: AnotherParadigm For The Double-Edged Role of Nitric Oxide” (Nitric Oxide 1(4):275-281, 1997) discusses the pro- and anti-apoptotic effects of nitricoxide.

In many instances it is desirable to prevent neointimal proliferationthat leads to stenosis or restenosis. U.S. Pat. No. 5,766,584 to Edelmanet al. describes a method for inhibiting vascular smooth muscle cellproliferation following injury to the endothelial cell lining bycreating a matrix containing endothelial cells and surgically wrappingthe matrix about the tunica adventitia. The matrix, and especially theendothelial cells attached to the matrix, secrete products that diffuseinto surrounding tissue, but do not migrate to the endothelial celllining of the injured blood vessel.

In the treatment of heart disease it is also important to determine theoverall effectiveness of the heart as a pump and the ability of theblood vessels to carry blood to other organs. If blood flow to an organis significantly restricted, the organ can be damaged, and if the flowis stopped, death may occur. Consequently, the measure of the flow ofblood within a blood vessel has been used as an indicator of thecondition of the blood vessel and the pumping action of the heart. Bymonitoring the blood flow of a patient, the early detection of a heartcondition, or of restenosis, is possible, and preventative measures maybe taken to address any problems. If the blood vessel becomes seriouslyclogged, angioplasty or a by-pass operation may be performed that uses agraft to circumvent the damaged vessel.

In overseeing the condition of a patient's blood vessel, a number ofblood flow measurements may be needed, over time, to effectively monitorthe patient's condition. One known method of monitoring the flow ofblood in a vessel involves the percutaneous application of an instrumentto measure the flow. Such methods are termed “invasive” because the bodymust be pierced to obtain the blood flow measurement. Clearly, invasivetechniques to measure blood flow have a disadvantage in that themeasurement must be taken under controlled conditions. For example, itis difficult, if not impossible, to monitor blood flow during periods ofincreased exercise.

Despite the progress of the art in providing implantable stents usefulfor treating a damaged body lumen, there is a need for new and betterstents, particularly for stents that are adapted to promote growth ofinfiltrating cells into organized cellular structures, such as takeplace during angiogenesis and/or neovascularization, to aid in repair ofa damaged body lumen. It is also apparent that a device thatnon-invasively measures the flow of blood in a blood vessel isdesirable.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery that neointimalproliferation can be promoted and turned to healing effect if theinfiltrating cells can be forced to assume an organized growth patternor by subjecting the cells to increased stress, such as temperature orfluid shear stress. Thus, contrary to present belief, in many instancesin which it is desirable to encourage regrowth of a damaged blood vesselor other body lumen, such as a tubular organ, the natural phenomenon ofneointimal proliferation occurring at a site of damage can betransformed from a cause of failure to a cause of healing.

Therefore, according to the present invention, there are providedstent(s) comprising a tubular stent body and having surface featuressized and/or arranged to promote an organized growth pattern ofinfiltrating cells. For example, a film of cells covering at least theinterior surface of the stent body may encourage ingrowth ofinfiltrating cells.

In many instances, the organized growth pattern develops into anorganized cellular structure within the stent body to aid in repair of adamaged body lumen. For example, in one embodiment, the surface featuresare selected to promote angiogenesis when the stent is implantedintravascularly. The surface features for promoting organized cellgrowth can comprise a plurality of depressions in the surface of atleast a portion of the stent body, preferably arranged in a regularpattern on at least the interior surface of the stent body, such as awaffle weave. In other embodiments, the surface features comprise aplurality of pleats, ridges, channels or pores in the stent body whereinat least some of the pores run between the interior and exterior sidesof the stent body (i.e., penetrate the stent body) and are sized topromote the organized cell growth.

In typical embodiments, the invention stent body is formed from abiocompatible polymer or a biocompatible metal with the surface featuresstamped or molded into the surface. For example, the invention stentbody can be formed of a porous biocompatible material, such as a porousmatrix of sintered metal fibers or a polymer wherein the pores are sizedto promote the organization of ingrowing cells therein. Preferably, theinvention stent is diametrically expandable for implant mounted uponsuch a device as a balloon catheter.

In other embodiments according to the present invention, there areprovided stents having a surface feature that creates or enhances acondition of turbulence in a fluid flowing through the tubular stentbody such that ingrowing cells are subjected to increased fluid shearstress by action of the turbulence, and/or the surface features createstagnant flow through the stent body sufficient to cause clotting ofblood, thereby promoting angiogenesis and/or neovascularization withinthe stent body when the stent is implanted intravascularly.

For example, in one embodiment, at least a portion of the stent body iscovered by a biocompatible substance that expands or thickens in anaqueous environment to assume a three-dimensional form that promotesturbulence within the stent body. The liquid-expandable substance can beapplied to the stent body in a pattern, for example, a pattern of dots,lines or curvilinear markings. In one embodiment, the biocompatiblesubstance is a biocompatible hydrogel, or a mixture thereof.Biocompatible hydrogels useful in manufacture of the invention stentsare those that provide an interpenetrating polymer network (IPN)structure, which upon expansion in an aqueous environment, ischaracterized by the presence of interconnecting pores. If the stentbody is itself formed of a fibrous mesh, there is communication betweencells external to the stent (i.e., in the vessel or lumen wall) via theholes or pores in the stent body and those growing within theinterconnecting pores of the hydrogel layer. Presently preferredhydrogels for use in fabrication of the invention stents arebiodegradable hydrogels consisting of hydrophobic biodegradablepolymers, (e.g., polylactide) and hydrophilic natural polymers (e.g.,dextran) with an interpenetrating polymer network structure.

The stent body is designed to promote infiltration and population of thestent by living cells, when the stent is cultured in a cell-rich mediumor when the stent is implanted into a blood vessel or other tubular bodylumen in a living subject, such as a mammal. Further the surfacefeatures in the stent body are selected to cause the living cells thatinfiltrate and populate the stent to undergo cell growth in a specificpattern determined by the placing and dimensions of the surface featuresof the stent body. One example of such pre-determined cell growthpattern is angiogenesis and/or neovascularization.

The invention stent optionally further comprises a transcutaneouslyenergized heating mechanism attached to the stent body. The heatingmechanism, which can be energized remotely (i.e., transcutaneously), isadapted to controllably heat cells within and surrounding the stent inthe lumen wall to a temperature sufficient to cause infiltrating cells,or cells seeded thereon prior to transplant, to increase production ofone or more bioactive agents, such as one or more anti-proliferative,anti-restenotic, apoptotic, or angiogenesis-stimulating agents. In oneembodiment according to the present invention wherein the inventionstent is implanted in a blood vessel, the heating mechanism includesfrom one to about six temperature sensors and is adapted to control theheating of the cells to an elevated temperature in the range of from 38°C. to about 49° C. However, in certain body lumens, such as the urinarytract, tracheobronchial tree, and the like, a temperature of 49° C.would cause damage. Therefore, those of skill in the art will be able toadjust the allowable maximum temperature to the body lumen beingtreated.

Upon application of external energy to the implanted stent, itstemperature can be elevated to promote the production of beneficialmolecules, such as nitric oxide, to effect a cessation of neointimalhyperplasia within the cells in the lumen wall and/or cells growingwithin the stent. Alternatively, the stent can be populated beforeimplant with cells engineered to express a bioactive agent that promotesa healing bodily process, such as angiogenesis and/orneovascularization. Suitable bioactive agents that can be obtained fromsuch genetically engineered cells include several growth factors, e.g.,platelet derived growth factor-A (PDGF-A), transforming growth factor(TGF), nuclear factor-κβ (NF-κβ), an inducible redox-controlledtranscription factor. In these studies, low levels of thermal therapyinhibited smooth muscle cell proliferation after balloon injury throughsuppression of growth factors PDGF-A and NF-κβ. If such cells are placedunder the control of a heat sensitive promoter, such as a heat shockprotein promoter, the heating mechanism can be used to switch on or offthe production of the bioactive agent upon application or withdrawal ofexternal energy to the implanted stent. Thus, the invention stent can beused in a number of different applications wherein it is desirable tochronically release a therapeutic substance from an implant, on demand,for example to cells within the wall of a damaged body lumen or tubularorgan.

Accordingly, in another embodiment according to the present invention,there are provided methods for treating a tubular body organ in asubject in need thereof. The invention treatment method comprisespromoting the ingrowth of living cells on a stent having surfacefeatures sized to promote ingrowth and/or orderly development of thecells, and implanting the stent into the tubular organ of the subjectprior to or following the promoting of the ingrowth of the living cellsso as to treat the tubular body organ. The living cells can be donor orautologous cells. The living cells can be provided by a donor or thecells can be autologous. The invention treatment method is particularlyuseful for promoting or inhibiting angiogenesis within the stent body.

In another embodiment, the invention stents are adapted for measuringthe flow of a fluid through the stent body. In this embodiment, theinvention stent comprises a tubular stent body and a transcutaneouslyenergized heating mechanism attached to the stent body that includes atleast two to about six temperature sensors attached at spaced locationsalong the length thereof, and a telemetering device for transcutaneouslytransmitting the output of the temperature sensors to an externalmonitor that records the output. Methods are provided for using theoutput from the temperature sensors to obtain the flow of a fluid, suchas blood, through the stent body.

Thus, it is an object of the present invention to provide an implantablestent that is adapted to promote angiogenesis within a blood vessel orother tubular lumen into which the stent is implanted.

It is a further object of the present invention to provide animplantable stent that is adapted to enhance or stimulate neointimalinfiltration, but with organization of the infiltrating cells so as toresult in neovascularization.

It is a further object of the present invention to provide animplantable stent that is adapted to promote ingrowth of living cells,when cultured in a cell-rich in vitro environment or when implantedwithin a tubular body lumen, such as a blood vessel.

It is a further object of the present invention to provide a stent thatcreates stagnant flow and/or enhances shear turbulence in blood flowingtherethrough when implanted into a blood vessel or other tubular bodylumen (as compared with that applied by a similarly composed stent, butlacking the surface features of the invention stent).

It is a further object of the present invention to provide a livingstent populated with living cells growing throughout pores and/or othersurface features designed to promote growth of the cells into anorganized cellular structure when the cell is implanted into a tubularbody lumen or organ.

It is a further object of the present invention to provide such a livingstent wherein the living cells are genetically engineered to produce atherapeutic bioactive agent, such as one selected to inhibit or promoteangiogenesis or proliferation of intima within the implanted stent.

It is a further object of the present invention to provide a stentwherein there is attached or affixed thereto a mechanism for controllingheating of the stent in response to a transcutaneously applied energysource.

DESCRIPTION OF THE DRAWINGS

The foregoing features, objects and advantages of the invention willbecome apparent to those skilled in the art from the following detaileddescription, especially when considered in conjunction with theaccompanying drawings in which like numerals in the several views referto corresponding parts.

FIG. 1 is a greatly enlarged cross-sectional view through an arteryshowing a stent positioned therein, the stent including elements and/orcircuitry for measuring and transmitting temperature information fromthe stent;

FIG. 2 is a greatly enlarged cross-sectional view of a preferredmaterial from which a stent like that shown in FIG. 1 may be formed;

FIG. 3 is a schematic block diagram of the system used with the stent ofFIG. 1;

FIG. 4 is a bar chart graph showing the percentage increase in cellproduction of heat shock protein and inducible nitric oxide synthaseresulting from the hyperthermia.

FIG. 5 is a graph showing the results of experiments conducted using theinvention heatable stent to measure the rate of flow of blood throughthe stent. The temperatures shown (° C.) are the average for four datapoints for three equidistant temperature sensors on the stent, with“distal stent” representing the sensor distal to the heating element and“proximal stent” representing the sensor proximal to the heatingelement. Flow rate was measured with flow from the distal to theproximal sensor (Flow Distal) and from the proximal to the distal sensor(Flow Proximal). −x−=distal stent−flow distal; ●=mid stent-flow distal;▪=mid stent−flow distal; ▪=mid stent−flow proximal; ♦=distal stent−flowproximal; ▴=proximal stent−flow distal.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there are provided stents comprisinga tubular stent body having surface features adapted to promote anorganized growth pattern of infiltrating cells, such as takes placeduring angiogenesis and/or neovascularization. For example, in oneembodiment the surface features comprise a plurality of depressions inthe surface of at least a portion of the stent body, for example theinterior surface of the stent body. It is presently preferred that thesurface depressions have an average volume per depression in the rangefrom about 10 μm to about 100 μm. The surface depressions are generallyarranged in an orderly pattern, such as a waffle weave pattern than canbe readily stamped into the material from which the stent body isfabricated.

In one embodiment according to the present invention, the inventionstent has surface features comprising pores in the stent body having anaverage diameter in the range from about 30 microns to about 65 microns.Generally the invention stent has a slightly greater inner diameter thanthat of the lumen into which it is placed such that a layer of ingrowingcells will cause the effective inner diameter to match the innerdiameter of the vessel or lumen into which it is placed. Cells growingin the stent (e.g. in pores contained in the stent) will extend outwardinto the lumen of the stent and grow into attachment with cells in thelumen at either end of the stent, forming a continuous live cellularcontact for fluid flow within the lumen of the stent. Since there wouldthen be no contact with a foreign object in the vessel, thrombosis andimmune response, which would tend to close the lumen of the stent withfibers and collagen, is reduced. Generally, the overall porosity of theinvention stent is in the range from about 50% to about 85%, forexample, at least about 70%.

It has been discovered that when the stent body is penetrated with poreshaving such an average diameter, the pores will be readily populatedwith living cells if the stent is cultured in a cell-rich medium (e.g.,6-10×10⁴ endothelial cells in 0.8 ml culture medium) undercell-culturing conditions, as is known in the art. Such a cell culturingprocedure is described, for example, in D. A. Dichek et al., supra,which is incorporated herein by reference in its entirety.Alternatively, if an invention stent having such pores is implanted intoa body lumen, for example intravascularly, the implanted stent willreadily be infiltrated by cells from the surrounding cellularenvironment so as to create an organized cellular structure similar tothat of the surrounding bodily environment. For example, the type oforganized structure formed within the stent may be dictated by thebiological environment surrounding the implanted stent (e.g. whether ablood vessel or a urethra). Alternatively, the type of organizedstructure formed will correlate with the type of cells seeded into thestent or that infiltrate the stent from the implant site.

Surprisingly, it has been discovered that pores in the size range fromabout 30 microns to about 65 microns are particularly effective forpromoting the growth and organization of infiltrating cells, such ascells of the vascular intima, into organized cellular structures, suchas takes place during angiogenesis and neovascularization.

In another embodiment according to the present invention, the inventionstent has surface features selected to organize the infiltrating cellsinto a longitudinal growth pattern. To promote this type of organizedcell growth, the surface features of the invention stent can comprise aplurality of longitudinal pleats, grooves, channels, and the like, inthe stent body (i.e., running along the axis of the tubular stent body).The pleats, grooves, or channels are preferably spaced and sized tocreate turbulence in flow of blood through the stent and/or to causelongitudinal alignment of cells that infiltrate the pleats, grooves,and/or channels. To encourage ingrowth of cells and cellular alignment,the pleats, grooves, or channels generally have an average height ordepth in the range from about 10 μm to about 100 μm and an averagedistance from center to center in the range from about 10 μm to about100 μm.

Alternatively, the surface features can be selected to create turbulencein a fluid, such as blood, flowing through the tubular stent body. Forexample, an undulating or uneven inner stent surface will enhanceturbulence within the stent. The turbulence created by the surfacefeatures is intended to apply increased fluid shear stress oninfiltrating cells (as compared with that applied by a similarlycomposed stent, but lacking the surface features of the invention stent)when the stent is implanted in the vasculature of a living body.Although the effect of fluid shear upon cell growth within a stent isnot completely understood, it is believed that higher shear forces uponneointimal and endothelia slow or stop the cell growth. The elevatedshear may force cells to mature earlier, the increased shear force beinga mechanical and fluid dynamic stimulus to maturation. Preferably thefluid shear stress is created in the longitudinal direction relative tothe stent.

In another embodiment according to the present invention, the inventionstent has a tapered inner diameter for restricting fluid flow in anozzle like manner, thereby tending to control cell growth by exertingincreased fluid shear on the ingrowing cells.

It has also been discovered that angiogenesis and neovascularization areenhanced when blood flow through an implanted stent is slowed downsufficiently to promote clot formation, as clot formation is an initialstep in the process leading to formation of new vasculature. Therefore,the surface features on the interior surface of the invention stent bodycan efficaciously be selected to promote stagnation of blood flowthrough the stent. There is evidence that smooth muscle cells migratefrom sites distant to colonize a resorbing thrombus, using it as abioabsorbable proliferation matrix in which to migrate and replicate.Typically, the thrombus is colonized at progressively deeper levelsuntil the neointimal healing is complete R. S. Schwartz et al.,“Biomimicry, vascular restenosis and coronary stents,” Semin IntervCardiol 3(3-4):151-6, 1998. Of course, formation of a thrombus can leadto downstream embolism. Therefore, care must be taken that thestagnation of flow is controlled in such a way as to avoid production ofan embolism, for example, by adjustment of (i.e., by increasing) thefluid shear stress on the blood cells within the stent.

To aid in the creation of turbulence within the stent body that exertsfluid shear stress in a longitudinal direction on infiltrating cells,the surface features on the stent body can comprise an array ofupstanding projections that promote or enhance shear turbulence in bloodflow along at least a portion of the surface of the stent body (ascompared with that applied by a similarly composed stent, but lackingthe surface features of the invention stent). Preferably the arraycovers at least the interior surface of the stent body. The projectionsgenerally have an average height of from about 10 μm to about 100 μm. Inone embodiment, the projections comprise an orderly array of hooks, suchas is used in Velcro® fasteners, or stalks having a diameter to heightratio of from about 10:1 to about 100:1. Generally such stalks have aflow impeding feature, such as a bulbous tip. The orderly array can havea uniform spacing of from about 10 μm to about 200 μm from center tocenter. Methods for fabricating a flexible backing having an array orsuch projections are disclosed in U.S. Pat. No. 5,879,604, which isincorporated herein by reference in its entirety.

In another embodiment according to the present invention, the surfacefeatures on the invention stent comprise a layer of a biocompatiblesubstance that expands or thickens in an aqueous environment to assume athree-dimensional form, wherein the layer covers at least a portion ofthe surface of the stent body. For example, the biocompatible substancecan be or comprise one or more hydrogels, such that the hydrogel layerexpands as it absorbs water upon contact with an aqueous environment tocreate a porous three dimensional layer. Alternatively, the threedimensional form can comprise an array of upstanding projections, suchas described above. In this case, it is preferred that the surfaces ofthe stent be relatively smooth (e.g., with the projections lyingrecumbent against the surface of the stent body or in an undevelopedstate) until such time as the stent is implanted and/or comes intocontact with an aqueous environment. For example, the projections can beformed from dots of a substance that expands upon contact with water,such as dots of hydrogel or calcium hydroxyapatite crystals upon atleast the interior surface of the stent body that expand upon contactwith an aqueous environment, thereby forming projections into theinterior void of the stent body. Such projections aid in slowing theflow of fluid through the stent body. In another embodiment according tothe present invention, the surface features on the invention stentcomprise a pattern of hydrogel markings on at least a portion of thesurface of the stent body, such as a pattern of dots, lines, curvilineartracings, or a mixture thereof. Preferably the markings are distributedover at least the interior surface of the stent body, but the pattern ofmarkings can also cover the exterior surface of the stent body.

The stent body can be formed of any suitable substance, such as is knownin the art, that can be adapted (e.g., molded, stamped, woven, etc.) tocontain the surface features described herein. For example, the stentbody can be formed from a biocompatible metal, such as stainless steel,tantalum, nitinol, elgiloy, and the like, and suitable combinationsthereof.

Preferred metal stents are formed of a material comprising metallicfibers uniformly laid to form a three-dimensional non-woven matrix andsintered to form a labyrinth structure exhibiting high porosity,typically in a range from about 50 percent to about 85 percent,preferably at least about 70 percent. The metal fibers typically have adiameter in the range from about 1 micron to 25 microns. The averageeffective pore size is in the stent body such that cellular ingrowthinto the pores and interstices is enhanced, for example having anaverage diameter in the range from about 30 microns to about 65 microns.A material having these desired properties that can be used inmanufacture of the invention stent is available from the BekaeartCorporation of Marietta, Ga., and sold under the trademark, BEKIPOR®filter medium.

Alternatively, the stent body can be formed of a biocompatible nonporous polymer or a polymer made porous by incorporating dissolvablesalt particles prior to curing thereof and then dissolving away the saltparticles to leave voids and interstices therein. The polymer may bebiostable or bioabsorbable, such as a number of medical grade plastics,including but not limited to, high-density polyethylene, polypropylene,polyurethane, polysulfone, nylon and polytetra-fluoroethylene. A porouspolymer stent body can be made having pores with an average diameter inthe range from about 30 microns to about 65 microns, by procedures knownin the art. For example, polymer granules can be ground down to obtainsmall particles of about 100 microns in diameter, mixed with salt, andcompressed into a compact form, for example using a jack, a plate and adie. The compressed forms are then placed in a pressure vessel andsubjected to a gas, such as carbon dioxide, at high pressure of about800 pounds per square inch until the gas dissolves into the polymer, thepressure is released rapidly, and the polymer particles expand and fusetogether, to yield a porous polymer. Finally, the salt is leached out ofthe polymer to obtain a polymer having up to about 85 percent porosity.

Autologous cells naturally invade the invention stent, particularly thesurface features thereof, following placement in a body lumen of a hostsubject and spontaneously generate an organized cellular structure thatvaries depending upon the cellular makeup of the bodily lumen into whichthe stent is implanted. Alternatively, endothelial or other suitablecells may be made to invade the stent in a cell culture lab to create aliving stent prior to implant, using methods known in the art. Forexample, a living stent can be obtained according to the inventionwherein the stent is populated with live cells selected from endothelialcells, smooth muscle cells, leukocytes, monocytes, epithelial cells,polymorphonuclear leukocytes, lymphocytes, basophils, fibroblasts, stemcells, epithelial cells, eosinophils, and the like, and combinations ofany two or more thereof. In the invention living stent, such cellsactually live within the surface features of the stent, such as thepores, grooves, channels, etc., and are not merely a surface coating, asmay be the case when a metal wire braided stent is used, or other stentlacking suitable surface features as disclosed herein.

To enhance in vitro invasion of selected live cells, the stent may firstbe coated with a suitable component, such as a protein like fibronectin,elastin, mucopolysaccharide, or other suitable extracellular matrixprotein. The thus-treated stent is placed in a cell culture dish and theselected living cells are allowed to form a coating on non-porous stentsand to invade the interior of a porous stent material. Once the stent ispopulated with living cells, it is ready for implant.

Without limitation, in overall size a typical intravascular stent mayhave an outer diameter in a range of from about 2.0 mm to about 6.0 mmand a wall thickness in a range from about 0.1 mm to about 12 mm, forexample about 0.1 mm to about 1.0 mm. The particular size, of course,depends on the anatomy where the stent is to be implanted.

In another embodiment, the invention stent is diametrically adjustable,being designed to be remotely introduced into a body cavity by the useof a catheter type of delivery system. Any of a variety of techniques ordesigns, as is known in the art, can be used for making the inventionstent diametrically expandable. For example, such designs are disclosedfor example in U.S. Pat. No. 5,059,211, which discloses an expandablestent made of a porous polymeric material. Alternatively, the stent bodycan be made of an expanded metal or plastic device having a fenestratedside wall to facilitate expansion thereof, as shown in FIG. 1. In yetanother embodiment, the stent may instead have a tubular configurationthat is pleated longitudinally prior to implant so as to exhibit areduced outside diameter to facilitate routing and placement thereof,but which may later be expanded to a diameter equal to or only slightergreater than the diameter of the blood vessel, body lumen, or tubularorgan at the treatment site. The stent may also have a rolled or braidedconstruction known in the art which can be expanded from a lesserdiameter to a larger diameter.

The diametrically expandable stent is designed to be implanted in acontracted form, for example, mounted on a partially expanded balloon ofa balloon catheter and then expanded in situ to contact the lumen wall.Although any appropriate ratio between the collapsed and expandeddiameters of the invention stent can be employed, depending upon thebody lumen into which the stent is to be placed, generally in thediametrically adjustable stent, the expanded diameter is at least about1.5 times the size of the collapsed diameter. Optionally, the inventionstent can be coated with a friction-reducing coating, for example ofcommingled hydrogel, to reduce friction during implant, as disclosed inU.S. Pat. No. 5,662,960.

Referring to FIG. 1, there is illustrated a greatly enlargedcross-sectional view, through an arterial blood vessel 10. Formed withinthe blood vessel is a stenotic lesion 12 that has been subjected toballoon angioplasty for establishing greater patency to the artery. Incarrying out the balloon angioplasty procedure, the blood vessel hasbeen damaged, and a stent 14 constructed of a material capable ofsupporting cellular growth thereon, has been implanted into the lumen ofthe blood vessel and expanded to abut the inner layer of the injuredblood vessel.

Stent 14 is preferably a balloon expandable device made of expandablemetal or braided wire, but also may be designed as a self-expandingstructure. It may also be fabricated from a composition of metallicfibers, uniformly laid to form a three-dimensional, non-woven structure,such as is shown in FIG. 2.

In accordance with the present invention, the invention stent may beused as part of a stent system which comprises, in addition to theinvention stent, an energy source for transcutaneously transmittingheating energy to the stent to raise the temperature of the implantedstent to a temperature above body temperature. The energy source isexternal to the subject and delivers electromagnetic energy to the stentin the form of radio frequency energy, microwave energy, a magneticfield, and the like. The percutaneously delivered electromagnetic energyis transformed to heat energy in the stent body itself, for examplethrough induction of Eddy currents or dielectric heating. Optionally,but preferably, delivery of energy to the stent, and consequentlyheating of the stent, is controlled by from one to about six heatsensors attached to the stent body that communicate percutaneously withthe energy source to regulate the heating of the stent to a safe level.Preferably the energy source can transmit sufficient energy to theimplanted stent to stimulate the live cells therein to increaseproduction of one or more bioactive agents, such as are effective tomodify vascular structure in the hematologic system. For example, if theingrowing cells produce heparin, a coating of heparin will be formed onthe stent surface that modifies platelet function.

For example, where a metal stent is employed, the energy source fortranscutaneously transmitting heating energy to the invention stent cancomprise a source of high frequency AC current, shown here as generator15, for externally applying an alternating electromagnetic field that istranscutaneously transmitted from generator 15 to the implanted stent 14so as to induce Eddy currents therein, thereby causing the temperatureof the stent to rise above normal body temperature. To avoid the needfor telemetry, if the stent is made of a suitable metal alloy exhibitinga Curie point at a desired maximum temperature of about 49° C. or less,no control need be maintained over the externally applied magnetic fieldbecause the heating of the stent will not increase above the pointcorresponding to the Curie point. Similarly, in the case of a polymerstent, the source of transcutaneously applied heating energy cancomprise a source of microwave energy, or another form of high frequencydielectric heating known in the art, for transcutaneoulsy generatingheat in the polymer stent.

In another embodiment according to the present invention, the inventionstent used in the stent system as disclosed herein further comprises athermostat/heat regulator for monitoring the temperature of theimplanted stent and regulating the temperature therein to avoidover-heating of the stent and cells living therein to a temperaturewhere cell necrosis occurs, as described above. For example, FIG. 1shows the thermostat/heat regulator as an electronic sensor andtelemetering device comprising antenna coil 16, which is wrapped aboutthe surface of the stent 14, the antenna coil being connected to ahybrid integrated circuit chip 18, which is also mounted on the surfaceof the stent. When the source of high frequency energy used in theinvention stent system to transcutaneously transmit energy to theinvention stent is a radio frequency generator, a portion of the RFenergy used in heating the stent 14 is picked up by the antenna coil 16and converted to a DC voltage for powering the electronics comprisingthe hybrid circuit. Alternatively, a metal stent body may itself act asan antenna and transfer energy to a temperature sensor sufficient toactivate the sensor and transmit temperature readings to atranscutaneous monitor, and the like.

FIG. 3 is a schematic diagram of a representative hybrid circuit and itshows an AC/DC converter 19 for producing a DC voltage for powering themicroprocessor 20. A temperature sensor, such as a thermistor bead 22,is applied to the microprocessor and more particularly to an on-chip A/Dconverter 24 to produce a binary signal train proportional to thedifference between stent temperature and body temperature.

A program for controlling the conversion of the analog output from thetemperature sensor 22 to a digital representation is stored in a ROMmemory 26 in the hybrid circuit 18 and the data may be transmitted to anexternal monitor/controller 28 by means of a telemetry link 30 ofconventional design known in the art. The monitor/controller will thenoperate to increase or decrease the energy being transcutaneouslydelivered to the stent by the high frequency AC generator such that thestent temperature can be maintained at a predetermined set-point valuepreviously programmed into the RAM memory 32 of the hybrid circuit 18.

The temperature sensor can be a passive heat sensor, such as atemperature sensitive crystal, affixed to the stent and when aninterrogation frequency is applied, via an external power source, suchas a generator, the crystal will resonate at a frequency that varieswith temperature.

Our experiments have shown that elevated temperatures in the range offrom about 38° C. to about 49° C. will induce production of positiveenzymes and bioactive agents as gene products in certain cells locatedin and near the stent. For example, heat shock proteins and NOS can begenerated in smooth muscle cells. At these temperatures, the formingneointimal cells in the surface features of the invention stent exhibitan upregulation of useful proliferation-inhibitory products as neointimaforms in the surface features (i.e. pores) of the stent and in thevessel wall contacted by the stent. However, temperatures in excess ofabout 49° C. may result in cell necrosis and terminate production ofbeneficial gene products. In addition, nitric oxide synthase, the enzymeknown to trigger production of nitric oxide in endothelial cells of thevasculature, among others, has been found to be a by-product ofhyperthermia and NO has been shown to be shown to produce apoptosisinhibiting proliferation of smooth muscle cells.

Experiments we have conducted have demonstrated that cyclic, low levelheat treatment reduced proliferation of cells following vascular injuryin an organ culture model of porcine coronary arteries. While the exactmechanism whereby intimal hyperplasia is reduced is not clear, it isknown to be related to smooth muscle cell proliferation, which, in turn,is controlled by several growth factors, e.g., platelet derived growthfactor-A (PDGF-A), transforming growth factor (TGF), nuclear factor-κβ(NF-κβ), an inducible redox-controlled transcription factor. In thesestudies, low levels of thermal therapy inhibited smooth muscle cellproliferation after balloon injury through suppression of growth factorsPDGF-A and NF-κβ.

The graph of FIG. 4 illustrates the up-regulation in a heat shockprotein, HSP70, and inducible nitric oxide synthase resulting from anincrease in the cell temperature from 37° C. to 43° C. Also shown is thecorresponding increase in apoptosis in smooth muscle cells.

Accordingly, in another embodiment of the present invention, there areprovided methods for treatment of a tubular body organ in a subject inneed thereof. The invention treatment method comprises promoting theingrowth of living cells in a stent having surface features sized and/orarranged to promote ingrowth of the cells, and implanting the stent intothe tubular organ of the subject prior to or following the promoting ofthe ingrowth of the living cells so as to treat the tubular body organ.The invention stent used in the treatment method holds the cells in aspecific pattern or stimulates the growth of the cells into an organizedgrowth pattern. Preferably, the organized growth pattern develops intoan organized cellular structure within the stent body, such as takesplace during angiogenesis and/or neovascularization. The living cellscan be either donor or autologous cells.

The stent of the present invention can be implanted using any surgicaltechnique known in the art as is dictated by the particular tubular bodyorgan to be treated. However, it is presently preferred to implant theinvention living stent by placing the device in an unexpanded form overa deflated balloon on the distal end of an intravascular catheter. Thecatheter is routed through the vascular system until the stent ispositioned adjacent to target tissue where the balloon is then inflatedto expand the stent against the wall of the blood vessel. Once the stentis lodged in place, the balloon is again deflated and the placementcatheter is withdrawn from the body.

The invention treatment method can be used to stimulate the-growthand/or repair of numerous tubular body organs, including, but notlimited to blood vessels, trachea, ureters, urethrea, the common bileduct, the bronchi, and the like. So long as the body lumen has notsuffered a circumferential lesion that completely destroys or disruptsthe integrity of the lumen, the invention stent can be used to repairmost types of injuries in a tubular body lumen, including tears, splits,and the like.

In another embodiment of the invention treatment method, wherein thestent further comprises a transcutaneously energized heating mechanism,the invention treatment method further comprises transcutaneouslyapplying energy to the stent, thereby heating the stent to a temperatureabove normal body temperature sufficient to cause the living cells toexpress one or more bioactive agents.

The invention treatment method can be self-administered. For example,after the stent has been placed into the body lumen, eitherpercutaneously or surgically, the subject can place the energy source onor next to the outer body surface proximal to the stent so as to placethe stent in the energy field. For example, if the stent has been placedinto a coronary artery, the subject would hold the energy source againstthe surface of the chest. If the stent comprises a thermostat/heatregulator as described herein, or as known in the art, the sensor in theimplanted stent will regulate the energy field produced by the energysource as needed to modulate the temperature of the stent andsurrounding tissue to the desired temperature range (i.e. above bodytemperature, but below the temperature at which necrosis will occur).

The treatment can comprise operating the energy source with the stent inthe energy field for a single period of time, or at repeated shortintervals, for example about 20 to 30 minutes per day. The treatment canbe continued in this manner for as long as desired, for example, over aperiod of weeks or even months.

The living cells ingrowing in the stent in the invention treatmentmethod, which produce beneficial bioactive agents can be autologouscells of the subject into which the stent is implanted, cells seededinto the stent prior to implant that naturally produce the desiredbioactive agent, or cells that are genetically modified to produce adesired bioactive agent. Living cells that naturally produce one or morebioactive agents useful in practice of the invention methods includeendothelial cells, smooth muscle cells, leukocytes, monocytes,polymorphonuclear leukocytes, lymphocytes, basophils, fibroblasts, stemcells, epithelial cells, eosinophils, and the like, and suitablecombinations thereof. Such cells can be either donor or autologouscells.

Alternatively, the cells used in the invention treatment method can beengineered to express and release a bioactive agent in response toheating above body temperature such that the recombinant gene productsare delivered to a site implanted with an invention stent. For example,a heat sensitive gene promoter can be operatively associated with a genethat encodes such a bioactive agent or a protein that regulatesproduction of a bioactive agent to regulate expression of the geneproduct. Heat sensitive gene promoters suitable for use in the inventionmethod include the E. Coli and Drosophila heat shock promoters, and thelike. Heating (even to low temperatures) can be made to either turn on,or turn off, the recombinant gene when the temperature is elevated,depending upon the selection of the transcription regulatory region,e.g., the promoter and other regulatory elements, as is known in theart. The temperature elevation may be achieved, as indicated above,utilizing an external energy source to transcutaneously (i.e.,non-invasively or potentially invasively) heat the stent material andproximal cells.

The recombinant promoter/gene combination DNA can be transfected intothe cells of interest near the implant site, or alternatively, may beeluted from the stent or implant device to transfect, locally, proximalcells. Cells may also be externally transfected with the heat sensitivepromoter and gene, and then implanted with the stent device, so thatheating the device following implant will activate (or inhibit) the geneproduct directly. Heating can be done chronically over time, beingavailable to the biologic site of interest as long as the recombinantcells survive at the implant site.

Optionally, the cells can be obtained from a donor or from the hostsubject to be treated, modified as above, and then reintroduced into thesubject to be treated. In a presently preferred embodiment, thetrnsplanted cells are “autologous” with respect to the subject, meaningthat the donor and recipient of the cells are one and the same.

Genetically modified cells are cultivated under growth conditions (asopposed to protein expression conditions) until a desired density isachieved. Stably transfected mammalian cells may be prepared bytransfecting cells with an expression vector having a selectable markergene (such as, for example, the gene for thymidine kinase, dihydrofolatereductase, neomycin resistance, and the like), and growing thetransfected cells under conditions selective for cells expressing themarker gene. To prepare transient transfectants, mammalian cells aretransfected with a reporter gene (such as the E. coli β-galactosidasegene) to monitor transfection efficiency. Selectable marker genes aretypically not included in the transient transfections because thetransfectants are typically not grown under selective conditions, andare usually analyzed within a few days after transfection.

Genes that encode useful bioactive agents that are not normallytransported outside the cell can be used in the invention if such genesare “functionally appended” to a signal sequence that can “transport”the encoded product across the cell membrane. A variety of such signalsequences are known and can be used by those skilled in the art withoutundue experimentation.

Gene transfer vectors (also referred to as “expression vectors”)contemplated for use herein are recombinant nucleic acid molecules thatare used to transport nucleic acid into host cells for expression and/orreplication thereof. Expression vectors may be either circular orlinear, and are capable of incorporating a variety of nucleic acidconstructs therein. Expression vectors typically come in the form of aplasmid that, upon introduction into an appropriate host cell, resultsin expression of the inserted nucleic acid.

Suitable expression vectors for use herein are well known to those ofskill in the art and include a recombinant DNA or RNA construct(s), suchas plasmids, phage, recombinant virus or other vectors that, uponintroduction into an appropriate host cell, result(s) in expression ofthe inserted DNA. Appropriate expression vectors are well known to thoseof skill in the art and include those that are replicable in eukaryoticcells and/or prokaryotic cells and those that remain episomal or thosewhich integrate into the host cell genome. Expression vectors typicallyfurther contain other functionally important nucleic acid sequencesencoding antibiotic resistance proteins, and the like.

The amount of exogenous nucleic acid introduced into a host organism,cell or cellular system can be varied by those of skill in the art. Forexample, when a viral vector is employed to achieve gene transfer, theamount of nucleic acid introduced can be increased by increasing theamount of plaque forming units (PFU) of the viral vector.

As used herein, the phrase “operatively associated with” refers to thefunctional relationship of DNA with regulatory and effector sequences ofnucleotides, such as promoters, enhancers, transcriptional andtranslational stop sites, and other signal sequences. For example,operative linkage of DNA to a promoter refers to the physical andfunctional relationship between the DNA and promoter such that thetranscription of such DNA is initiated from the promoter by an RNApolymerase that specifically recognizes, binds to, and transcribes theDNA.

Preferably, the transcription regulatory region may further comprise abinding site for ubiquitous transcription factor(s). Such binding sitesare preferably positioned between the promoter and the regulatoryelement. Suitable ubiquitous transcription factors for use herein arewell-known in the art and include, for example, Sp1.

Exemplary eukaryotic expression vectors include eukaryotic constructs,such as the pSV-2 gpt system (Mulligan et al., (1979) Nature,277:108-114); pBlueSkript® (Stratagene, La Jolla, Calif.), theexpression cloning vector described by Genetics Institute (Science,(1985) 228:810-815), and the like. Each of these plasmid vectors iscapable of promoting expression of the gene product of interest.

Suitable means for introducing (transducing) expression vectorscontaining heterologous nucleic acid constructs into host cells toproduce transduced recombinant cells (i.e., cells containing recombinantheterologous nucleic acid) are well-known in the art (see, for review,Friedmann, Science, 244:1275-1281, 1989; Mulligan, Science, 260:926-932.1993, each of which are incorporated herein by reference in theirentirety). Exemplary methods of transduction include, e.g., infectionemploying viral vectors (see, e.g., U.S. Pat. Nos. 4,405,712 and4,650,764), calcium phosphate transfection (U.S. Pat. Nos. 4,399,216 and4,634,665), dextran sulfate transfection, electroporation, lipofection(see, e.g., U.S. Pat. Nos. 4,394,448 and 4,619,794), cytofection,particle bead bombardment, and the like. The transduced nucleic acid canoptionally include sequences which allow for its extrachromosomal (i.e.,episomal) maintenance, or the transduced nucleic acid can be donornucleic acid that integrates into the genome of the host.

Bioactive agents suitable for delivery according to the inventionmethods include those which the mammalian body utilizes to stimulateangiogenesis, including those which regulate capillary formation inwounds and attract smooth muscle to coat and support the capillaries.Examples of such bioactive agents include vascular endothelial growthfactor (VEGF), fibroblast growth factors (FGFs), particularly FGF-1,angiopoietin 1, thrombin, and the like. Additional examples of bioactiveagents suitable for delivery according to the invention methods includeanti-proliferative, anti-restenotic or apoptotic agents, such asplatelet-derived growth factor-A (PDGF-A), transforming growth factorbeta(TGF-β), nuclear factor-κβ (NF-κβ, an inducible redox-controlledtranscription factor, and the like.

In another embodiment according to the present invention, there areprovided temperature-sensing stents for measuring the flow of a liquid,such as blood, through the stent. The invention temperature sensitivestent is based upon the principle that a liquid (e.g., blood) flowingthrough stent is a cooling medium and that the amount of cooling of astent that has been heated above body temperature is directlyproportional to the flow rate of the liquid flowing through the stent.When the stent is implanted in a blood vessel, the inventiontemperature-sensitive stent can be used to measure and monitor the flowof blood in the blood vessel in a non-invasive manner.

The invention temperature-sensitive stent comprises a tubular stent bodyhaving attached thereto a heating mechanism that includes one to aboutsix temperature sensors, with the temperature sensors attached atdiscrete spaced locations along the length thereof, each adapted forsensing the temperature at the discrete location, and a telemeteringdevice for transcutaneously conveying the temperature sensed by eachsensor to a monitor. Optionally, the monitor can transform the messagefrom the telemetering device to a visible display, or record the messagein some other readable format. The monitor generally is in communicationwith the energy source so that temperature information from the sensorsis used to turn the energy source on and off to modulate and/or controlthe temperature of the invention stent.

Generally the stent comprises from two to about six with the temperaturesensors spaced out along the length of the stent body. For example, thestent may comprise three heat sensors equally spaced along the length ofthe stent body. It is preferred that the temperature sensors havesufficient sensitivity to detect a temperature difference as small as0.1° C. from one end of the stent to the other end. When the temperaturesensor is a thermocouple or thermopile, temperature differences as smallas 0.1° C. can be detected.

The invention temperature-sensing stent may further comprise surfacefeatures in the stent body adapted to promote an organized growthpattern of infiltrating cells as described herein.

In another embodiment, methods are provided for using the inventiontemperature-sensing stent to measure flow of a fluid through a bodylumen into which the stent is implanted, for example blood flow througha blood vessel. The invention method for measuring flow of a fluidcomprises implanting an invention stent temperature-sensitive stent, asdescribed herein, into a body lumen having a flow of fluid therethrough,energizing the implanted stent transcutaneously to raise the temperaturethereof above body temperature, monitoring transcutaneously the outputfrom one or more of the temperature sensors upon cessation of theenergizing to determine the cooling rate at the sensors, and obtainingthe flow rate of the fluid from the cooling rate at the one or moresensors. To be useful in measuring the flow rate of fluid through theimplanted stent, the stent body is generally sufficiently to raise thetemperature of the stent about 2 to 12 degrees Centigrade above bodytemperature.

Determination of the fluid flow rate from the temperature information(e.g., the cooling rate of the fluid flowing through the stent) providedby the temperature sensors via the telemetry in the stent involvesapplication of one or more mathematical algorithms, such as are wellknown in the art. Such algorithms generally take into account suchparameters as the heat capacity properties of the fluid, the interiorcross-sectional area of the stent body, the length of the stent, thedistance between the relevant temperature sensors, the differencebetween temperatures sensed at any two locations along the length of thestent, the difference between the temperature sensed at any discretelocation and body temperature, the neointimal thickness/area, and thelike. When the fluid whose flow rate is to be determined is blood, theheat capacity of the blood may vary by patient when such factors ashematocrit, and the like, are taken into account. Equation I below canbe used to obtain a fluid flow rate based on such parameters as follows:dT/dx=(ρ_(o) P)A/Q  (I)wherein T=temperature; x=distance of fluid flow; ρ_(o)=specific heat offluid; P=power in to heat the stent; Q=flow rate; and A=cross-sectionalarea of the stent.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

EXAMPLE 1

Temperature vs. Variable Flow Rates

The concept of flow measurement by the temperature sensitive stent isbased upon the principle that a liquid (e.g. blood) flowing through astent is a cooling medium and that the amount of cooling of a stent thathas been heated above body temperature is directly proportional to theflow rate of the liquid through the stent. This is expressed by EquationI above. To validate the use of the heated stent as a measure of flowrate, experimental data was obtained through the bench testing asfollows.

A GR2 type configuration stent was created using 38 AWG Nichromeresistance wire. 30 AWG Type J thermocouples were attached to the stentin three locations described as distal (furthest away from stent heatingleads), mid and proximal. The stent was deployed in a simulated bloodvessel made of silicone and submerged in a 37° C. distilled water bath.The water bath temperature was held constant during the testing. While aconstant voltage of 11 V was applied to the stent leads, 37° C.distilled water was pumped via a peristaltic pump through the deployedstent/vessel assembly at flow rates of 10, 20, 30, 40, 50, 60, 70, 80ml/min while temperature data was collected from each of the threethermocouples. The direction of the flow was then reversed and data wasagain collected for these flow rates. Temperature measurements wererecorded for a total of three minutes. Four data points for each stentlocation were collected per minute. The data shown in Tables 1 and 2below is the average of these four data points. The first three datapoints at each location were thrown out (time for stent temp to ramp to11 V≈40 sec). FIG. 5 is a graph showing the average temperature plottedagainst flow rate (ml/min) for each of the three thermocouples. TABLE 1Flow Proximal to Distal Distal Stent - Proximal Stent - Flow Distal MidStent - Flow Flow Distal Flow Rate Average Temp Distal Average AverageTemp (ml/min) (° C.) Temp (° C.) (° C.) 10 56.66 51.36 45.59 20 50.3546.12 42.76 30 47.36 44.68 41.84 40 44.33 42.50 40.92 50 43.67 41.8040.40 60 43.06 41.25 40.07 70 42.47 40.73 39.79 80 41.64 40.47 39.31

TABLE 2 Flow Distal to Proximal Proximal Distal Stent - Flow Mid Stent -Flow Stent - Flow Flow Rate Proximal Average Proximal Average ProximalAverage (ml/min) Temp (° C.) Temp (° C.) Temp (° C.) 10 45.66 49.9452.36 20 43.63 46.29 48.93 30 42.34 44.42 46.71 40 41.27 42.80 44.35 5040.86 42.87 44.59 60 40.49 42.41 43.76 70 40.14 42.08 42.91 80 39.9941.67 42.45The values obtained from theoretical calculations using Equation I abovecorrelated well with values obtained by these empirical tests.

This invention has been described herein in considerable detail in orderto comply with the patent statutes and to provide those skilled in theart with the information needed to apply the novel principles and toconstruct and use such specialized components as are required. However,it is to be understood that the invention can be carried out byspecifically different equipment and devices, and that variousmodifications, both as to the equipment, operating procedures and enduse, can be accomplished without departing from the scope of theinvention itself as defined by the appended claims.

1. An implantable stent comprising a tubular stent body having aplurality of interconnected microholes distributed throughout said stentbody substantially uniformally along the entire length of said stentbody, said plurality of microholes being sufficiently small so as topromote an organized growth pattern of infiltrating cells throughoutsaid stent body, and said stent body being otherwise substantially freeof holes larger than said microholes.
 2. The stent according to claim 1wherein the organized growth pattern is angiogenesis.
 3. The stentaccording to claim 1 wherein the stent is diametrically adjustable. 4.An active stent comprising a stent according to claim 1 and furthercomprising live cells growing in said interconnected microholes.
 5. Theactive stent according to claim 4 wherein the live cells are selectedfrom the group consisting of endothelial cells, smooth muscle cells,leukocytes, monocytes, epithelial cells, polymorphonuclear leukocytes,lymphocytes, basophils, fibroblasts, stem cells, epithelial cells andeosinophils.
 6. The active stent according to claim 5 wherein the livecells are smooth muscle cells, epithelial cells, or endothelial cells.7. A method for treating a tubular body organ in a subject in needthereof said method comprising: promoting the ingrowth of living cellsin a stent having a plurality of interconnected microholes distributedwithin said stent body substantially uniformally along the entire lengthof said stent body, said plurality of microholes being sufficientlysmall in size so as to promote ingrowth of the cells, and said stentbody being otherwise substantially free of holes larger than saidmicroholes, and, implanting the stent into the tubular organ of thesubject prior to or following the promoting of the ingrowth of theliving cells so as to treat the tubular organ.
 8. The method accordingto claim 7 wherein the living cells are donor or autologous cells. 9.The method according to claim 8 wherein the living cells are autologous.10. The method according to claim 7 wherein the treatment furthercomprises promoting or inhibiting angiogenesis within the stent body.11. The method according to claim 7 wherein the body organ is a bloodvessel.
 12. The method according to claim 7 wherein the treatingcomprises holding the cells in a specific pattern or stimulating thegrowth of the cells into an organized growth pattern.
 13. The methodaccording to claim 12 wherein the organized growth pattern develops intoan organized cellular structure within the stent body.
 14. The methodaccording to claim 7 wherein the living cells are endothelial cells,smooth muscle cells, leukocytes, monocytes, polymorphonuclearleukocytes, lymphocytes, basophils, fibroblasts, stem cells, epithelialcells or eosinophils.
 15. The stent according to claim 1, wherein saidstent body is penetrated with said microholes.
 16. The stent accordingto claim 1, wherein said stent body is formed from a three dimensionalnon-woven matrix.
 17. The stent according to claim 1, wherein saidmicroholes extend throughout said stent body so as to promote cellgrowth outward into said stent tube and into attachment with cells ateither end of said stent.
 18. The method according to claim 7, whereinsaid stent body is penetrated with said microholes.
 19. The methodaccording to claim 7, wherein said stent body is formed from a threedimensional non-woven matrix.
 20. The method according to claim 7,wherein after the implanting of said stent, said ingrowth of livingcells is promoted such that said cells grow outward into said stent tubeand into attachment with cells at either end of said stent.